The role of nanomedicine in cell based therapeutics in cancer and inflammation.

Cell based therapeutics is one of the most rapidly advancing medical fields, bringing together a range of fields including transplantation, tissue engineering and regeneration, biomaterials and stem cell biology. However, traditional cell-based therapeutics have many limitations, one of which is their harmful effects exhibited on healthy body cells due to their lack of specificity. Nanomedicine is providing an alternative treatment strategy that is more targeted and specific to a range of diseases. Varying from polymers conjugated with drugs or tissue targeting molecules, to proteins encapsulated within a polymer shell, nanomedicine will without a doubt play a major role in designing effective cell-based therapeutics that can overcome certain classical problems. These may include from addressing the problem of non-specificity of contemporary treatments to overcoming mechanical barriers, such as crossing cell membranes. This review summarises the recent work on nano-based cell therapy as a regenerative agent and as a therapeutic for cancer and neurological diseases.

PEGylation of nanoparticles allows them to escape the reticulo-endothelial system, which is a significant biological barrier (8).  Research is also being undertaken to use gold nanoparticles to enhance the radiofrequency thermal destruction of human gastrointestinal cancer cells non-invasively. Radiofrequency ablation (RFA) is currently used to treat some malignant tumours, however it is an invasive procedure with only a ~60% success rate. The treatment is also non-specific, with normal tissues also being damaged in many cases (24).
Gold nanoparticles were selected to develop a non-invasive, more targeted radiofrequency therapy. Gold nanoparticles were chosen because of the above mentioned properties, as well as their anti-angiogenic properties. It was proposed in the study that gold nanoparticles would release significant amounts of heat when exposed to a radiofrequency field. Gannon et al. (2008) performed an in vitro study that showed the success of gold nanoparticles in this application. They were taken up by cells in culture, and localized in vesicles within the cytoplasm. The gold nanoparticles did not produce any cytotoxic effects and did not seem to affect proliferation of the cells.
The cells with gold nanoparticles were exposed to an external radiofrequency source, and the nanoparticles released significant amounts of heat.
This exposure produced a dose-dependent lethal injury in >96% of the targeted cells (24). These results show promise for in vivo studies and potential clinical applications in the treatment of a range of malignant tumours. Table 1 shows the various anti-cancer drugs and the nanoformulations used to target different cancers.

Cancer Stem Cells
Another landmark on the road to curing cancer has been the discovery of cancer stem cells The development of these therapies holds promise for tumour suppression, and a significant reduction in cancer relapse after the surgical removal of tumours, if CSC therapy is found to be a viable post-surgical treatment option.

Nanomedicine and neurological diseases
The primary obstacle in the treatment of diseases affecting the (CNS) is the Blood Brain Barrier (BBB). The BBB is composed of brain endothelial cells and separates the brain from the rest of the systemic circulation. It is the major route of entry for drugs into the CNS. The main role of the BBB is to maintain homeostasis of ions for normal neuronal function, to supply the brain with nutrients and protect it from toxic agents.
The restriction of transport into the brain is through physical tight junction barriers, as well as through the use of enzymes as a metabolic barrier (Fig.2

) (30).
Molecules can cross the BBB to enter the brain interstitial fluid either through lipid-mediated transport by free diffusion of micromolecules, or facilitated transport of micro and macro-molecules.
The BBB and the Blood-CSF-Barrier both have efflux transport systems that can also remove substances from either the brain or the CSF and transfer them out to the systemic circulation (30).
Once molecules have crossed the BBB into the cerebrum they are rapidly and extensively distributed throughout the brain, due to the high vascular density in the brain. When designing nanocarriers to cross the BBB, modifications such as recognition ligands and ligands to enhance transcytosis need to be considered Liposomes can also be coupled with mannose, transferrin or insulin receptors to cross the BBB.
The transferrin receptor in particular is more highly expressed in the BBB during certain pathologies, in this case after a stroke. It has been shown in a rat model that transferrin-conjugated liposomes could specifically target the post-ischemic brain endothelium after a stroke (32).
Nanoparticles coated with a PEG-containing surfactant have been used to deliver a range of drugs to the CNS, including analgesics, anticonvulsants and anti-cancer agents (31) (  A healthy blood brain barrier has intact tight junctions to prevent unmediated passage of molecules into the brain, whereas a diseased blood brain barrier can have defective tight junctions, becoming 'leaky', and allowing molecules, unrestricted entry into the brain endothelium. Micelles have been conjugated to antibodies, either against brain α2-glycoprotein or insulin as targeting bodies. They were both shown to deliver either a drug or a fluorescent probe to the brain, and when haloperidol was solubilised in micelles it was shown to have a much higher neuroleptic activity than as a free drug (31). It has been shown that in brain microvessel endothelial cells, insulin modified micelles undergo receptor-mediated transcytosis to cross from the blood into the brain (31 which is induced by metals in the brain. These Dpenicillamine loaded nanoparticles resolubulized the β-amyloid plaques after easily crossing the BBB due to the polymeric nanoparticles (33). This resolubilization will slow, and potentially reverse, Neurodegenerative disorders are also becoming more prominent in today's aging society, and so there is much research being undertaken to develop methods of getting drugs across the BBB into neural tissue to treat these disorders.
Nanomedicine is thus developing into a seemingly limitless field to detect, diagnose and treat a huge range of diseases and disorders.